The goal of this project is to study the function of four genes in rodent models of binge drinking and ethanol dependence. The genes include Lmo3 and Lmo4, which encode transcriptional regulators, Alk, which encodes a receptor tyrosine kinase, and Mdk, which encodes a ligand that regulates the Alk gene product. Preliminary work in the investigator's laboratory and in the laboratories of other members of the INIA-West consortium suggests that these four genes cooperate to regulate behaviors associated with excessive alcohol consumption. The proposed work includes four types of experiments: (1) behavioral studies in genetically engineered mice to critically test the role of these four genes in alcohol-related behaviors, (2) experiments to map the brain regions where these genes function, (3) experiments to determine if alcohol affects the expression and function of these genes, and (4) experiments to identify downstream pathways by which these genes exert their effects. The work will provide basic insights into the role of a new signaling pathway in controlling behaviors that model human alcohol abuse. In addition, some of the genes in the pathway are protein kinases, which are regarded as excellent targets for drug development. Successful accomplishment of the project will thus lay the groundwork for development of totally novel, and much needed, pharmacotherapies for alcohol abuse in humans. PUBLIC HEALTH RELEVANCE: Alcohol use disorders place a tremendous burden on individuals and society. The few available treatments have only limited efficacy. The proposed work will advance our basic understanding of a novel pathway that regulates behaviors associated with excessive drinking and identify targets for the development of much needed therapies.